Phenoxy acetic acids and phenyl propionic acids as PPARδ agonists

Abstract

Phenoxy acetic acids and phenyl propionic acids and their use in treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, or obesity are provided herein. The present compounds are activators of PPARδ and may be useful for treating conditions mediated by the same.

The invention claimed is: 
     
       1. A method of arresting development of a disease-state, slowing development of a disease state, causing regression of a disease-state, or causing regression of a symptom of a disease-state, wherein the disease-state is type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein   is a double bond, with either E or Z substitution; 
         X 1  is C 1-6 -alkyl substituted with morpholino; 
         X 2  is phenylene; 
         X 3  is phenyl substituted with one or more halogens; 
         Ar is phenylene optionally substituted with methyl; 
         Y 1  is O; 
         Y 2  is O; 
         Z is CH 2 ; 
         R 1  is H; and 
         R 2  is H. 
       
     
     
       2. The method of  claim 1 , wherein X 1  is morpholin-4-ylmethyl. 
     
     
       3. A method of arresting development of a disease-state, slowing development of a disease state, causing regression of a disease-state, or causing regression of a symptom of a disease-state, wherein the disease-state is type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of:
 (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid; and 
 (Z)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
       4. The method of  claim 3 , wherein the compound is (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       5. The method of  claim 3 , wherein the compound is (Z)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       6. A method of arresting development of a disease-state, slowing development of a disease state, causing regression of a disease-state, or causing regression of a symptom of a disease-state, wherein the disease-state is type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein   is a double bond, with either E or Z substitution;
 X 1  is C 1-6  alkyl substituted with morpholino; 
 X 2  is phenylene; 
 X 3  is phenyl substituted with one or more halogens; 
 Ar is phenylene optionally substituted with methyl; 
 Y 1  is O or S; 
 Y 2  is CH 2 ; 
 Z is —CH 2 —; 
 R 1  is hydrogen; and 
 R 2  is hydrogen. 
 
       
     
     
       7. The method of  claim 6 , wherein X 1  is morpholin-4-ylmethyl. 
     
     
       8. The method of  claim 6 , wherein the compound is (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic acid or a pharmaceutically acceptable salt thereof. 
     
     
       9. The method of  claim 6 , wherein the compound is (Z)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic acid or a pharmaceutically acceptable salt thereof. 
     
     
       10. A method of arresting development of a disease-state, slowing development of a disease state, causing regression of a disease-state, or causing regression of a symptom of a disease-state, wherein the disease-state is type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound of selected from the group consisting of:
 (Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid; 
 (E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)-allyloxy]phenoxy]acetic acid; 
 (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid; 
 (E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid; and 
 (Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       11. The method of  claim 10 , wherein the compound is (Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       12. The method of  claim 10 , wherein the compound is (E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)-allyloxy]phenoxy]acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       13. The method of  claim 10 , wherein the compound is (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       14. The method of  claim 10 , wherein the compound is (E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       15. The method of  claim 10 , wherein the compound is (Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.